Double esters

ABSTRACT

The invention provides acyloxymethyl esters of C 6-14  alkane-dicarboxylic acids, or physiologically tolerable salts or esters thereof, for use in medicine as therapeutic or prophylactic agents.

This invention relates to certain double ester compounds, theirpreparation and their use, in particular by topical, oral or parenteraladministration as antibiotics or in the treatment of cancer.

Various alkane-dicarboxylic acids are known to have biologicalproperties useful in therapy and prophylaxis. One example of such adicarboxylic acid is the linear alkane-α,ω-dicarboxylic acid known asazelaic acid (C₉H₁₆O₄—nonanedioic acid or heptane-1,7-dicarboxylicacid). The primary medical use of azelaic acid is in the treatment ofacne where it is applied topically in the form of a 20% cream (e.g.Skinoren®, available from Schering A G, Berlin, Germany).

Topical application of azelaic acid helps to normalise keratinisationand to reduce proliferation of Propionibacterium acne, i.e. it exhibitsboth anti-inflammatory and antibiotic properties. Moreover, unlike manyantibiotics, it does not induce bacterial resistance.

Clinical studies have shown azelaic acid to have other beneficialtherapeutic effects. Thus for example it is relatively effective in thetreatment of papulopustular rocasea, in the treatment ofhyperpigmentation, as an antibacterial against Staphylococcusepidermidis and Staphylococcus aureus, as an antimycotic agent againstCandida albicans, Candida glabrata, Pityrosporum ovale and againstspecies of Trichophyton, and as an antitumor agent or as an enhancer ofcytotoxicity of other anti-cancer agents, in the treatment ofandrogenetic alopecia, etc.

However azelaic acid has relatively low efficacy in topical treatment ofacne (for which reason it is present in the very high concentration of20% in the commercially available creams—most dermatological creamscontain less than 5% of their active ingredient) and local adverseeffects, e.g. a burning sensation, are not uncommon.

Azelaic acid moreover has relatively poor biological uptake andbioelimination properties. Thus administered topically only about 3.6%of the dose is absorbed, while administered orally only about 60% isabsorbed. Furthermore 60% of absorbed azelaic acid is excreted into theurine within 12 hours.

There is thus a need for improved ways of presenting azelaic acid, inparticular ways which would enable the required dosages and/or treatmenttimes to be reduced.

It has been proposed to administer azelaic acid and other dicarboxylicacid drug compounds in the form of their esters; however there are noreports of such esters as having been demonstrated to have beneficialproperties, indeed Wilkerson et al. reported in Arch. Dermatol. 126:252-253 (1990) that azelaic acid esters did not depigment guinea pigskin.

We have now surprisingly found that alkane-dicarboxylic acid doubleesters have improved properties relative to the alkane-dicarboxylic aciditself.

A double ester is a term used for a compound containing anacyloxymethyloxycarbonyl group and such compounds are also referred toas acetal esters.

One double ester of azelaic acid is known from the literature as anactivator for hydrogen peroxide in bleach compositions—this isbis(1-(acetyloxy)ethyl)-nonanedioate (see EP-A-125781 and EP-A-122763).This double ester is not however described as having any pharmaceuticalutility.

Thus viewed from one aspect the invention provides acyloxymethyl estersof C₆₋₁₄ alkane-dicarboxylic acids, or physiologically tolerable saltsor esters thereof, for use in medicine as therapeutic or prophylacticagents.

Viewed from a further aspect the invention provides acyloxymethyl estersof C₆₋₁₄ alkane-dicarboxylic acids, other thanbis(1-(acetyloxy)ethyl)nonanedioate, and physiologically tolerable saltsand esters thereof.

The term acyl as used herein means a group attached via anoxo-substituted atom, preferably a carbon atom, e.g. a carbonyl-attachedgroup. The atom α to the carbonyl group is preferably carbon but mayalso be oxygen; i.e. the term “acyloxymethyl” may includealkoxycarbonyloxymethyl. In the compounds of the invention the acylgroup preferably contains 2 to 16 carbon atoms.

The alkane-dicarboxylic acids used in the present invention are C₆ toC₁₄ dicarboxylic acids, in particular C₈ to C₁₀ dicarboxylic acids,especially C₉ dicarboxylic acids. The molecular backbone linking thecarboxyl groups may be linear, branched or cyclic or a mixture thereof;however it is especially preferred that the acids be n-alkane-α-ω-dioicacids, i.e. with carboxyl groups at either end of a linear (CH₂)_(n)group.

In a preferred embodiment therefore the compounds of the invention arecompounds of formula I

(where n is an integer having a value of 4 to 12, preferably 6, 7 or 8,most preferably 7;

-   -   R¹ is hydrogen, an optionally substituted, optionally        unsaturated C₁₋₁₅ alkyl group, or, preferably, a group        —CHR³—O—CO—R²;    -   each R² independently is an optionally substituted, optionally        unsaturated C₁₋₁₅ alkyl or alkoxy group or together with the R³        γ to it is a 2 to 5 backbone atom bridging group;    -   and each R³ independently is hydrogen, an optionally        substituted, optionally unsaturated C₁₋₁₅ alkyl group, a group        R²—CO—O— or together with R² forms a bridging grouop as defined        above), and physiologically tolerable salts thereof.

In the compounds of formula I, R² may also represent an aryl, aralkyl,alkaryl, aryloxy, aralkoxy or alkaryloxy group (especially an aryl oraralkyl group) containing up to 16 carbons, e.g. a phenyl, benzyl, etcgroup.

The alkyl groups in the compounds of formula I are preferably branched,linear or cyclic C₁₋₇, more preferably C₁₋₆, alkyl groups and may beoptionally substituted, e.g. with one or more hydroxyl groups, oxogroups, halo atoms (e.g. F or Cl), alkoxy groups (e.g. C₁₋₆ alkoxygroups), acyloxy (e.g. C₁₋₆ alkanoyloxy) groups, thiol groups, aminogroups, aromatic groups (e.g. C₆₋₁₀ aryl groups), alkylthio (e.g. C₁₋₆alkylthio) groups, alkylamino (e.g. C₁₋₆ alkylamino or N—(C₁₋₆alkyl)-C₁₋₆-alkylamino) groups, etc.

Preferred examples of R³ groups include hydrogen, methyl, ethyl, propyland bridging groups, especially hydrogen and methyl. Preferred examplesof R² groups include methyl, ethyl, propyl, butyl (e.g. n-butyl ort-butyl), pentyl, benzyl, methoxy, ethoxy, propyloxy, butoxy, pentoxy,benzyloxy, phenyl and heptyl. Preferred examples of R¹ groups includeC₁₋₁₀ alkyl (especially methyl and ethyl) and —CHR³—O—CO—R² groups,especially the latter.

Especially preferably in the compounds of formula I n is 7, 8, 9 or 10;R² is C₂₋₆ alkyl or alkoxy or phenyl; R³ is H or methyl; and R¹ is CH₃or CHR³OCOR².

Examples of particularly preferred compounds of formula I include thefollowing:

-   bis[(acetyloxy)methyl]hexanedioate-   bis[(trifluoroacetyloxy)methyl]hexanedioate-   bis[(propionyloxy)methyl]hexanedioate-   bis[(butyryloxy)methyl]hexanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]hexanedioate-   bis[phenylacetyloxy)methyl]hexanedioate-   bis[(stearoyloxy)methyl]hexanedioate-   bis[(methoxycarbonyloxy)methyl]hexanedioate-   bis[(ethoxycarbonyloxy)methyl]hexanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]hexanedioate-   bis[1-(acetyloxy)ethyl]hexanedioate-   bis[1-(trifluoroacetyloxy)ethyl]hexanedioate-   bis[1-(propionyloxy)ethyl]hexanedioate-   bis[1-(butyryloxy)ethyl]hexanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]hexanedioate-   bis[1-(phenylacetyloxy)ethyl]hexanedioate-   bis[1-(stearoyloxy)ethyl]hexanedioate-   bis[1-(methoxycarbonyloxy)ethyl]hexanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]hexanedioate-   bis[benzoyloxymethyl]hexanedioate-   bis[hexanoyloxymethyl]hexanedioate-   bis[octanoyloxymethyl]hexanedioate-   hexanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   hexanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]heptanedioate-   bis[(trifluoroacetyloxy)methyl]heptanedioate-   bis[(propionyloxy)methyl]heptanedioate-   bis[(butyryloxy)methyl]heptanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]heptanedioate-   bis[phenylacetyloxy)methyl]heptanedioate-   bis[(stearoyloxy)methyl]heptanedioate-   bis[(methoxycarbonyloxy)methyl]heptanedioate-   bis[(ethoxycarbonyloxy)methyl]heptanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]heptanedioate-   bis[1-(acetyloxy)ethyl]heptanedioate-   bis[1-(trifluoroacetyloxy)ethyl],heptanedioate-   bis[1-(propionyloxy)ethyl]heptanedioate-   bis[1-(butyryloxy)ethyl]heptanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]heptanedioate-   bis[1-(phenylacetyloxy)ethyl]heptanedioate-   bis[1-(stearoyloxy)ethyl]heptanedioate-   bis[1-(methoxycarbonyloxy)ethyl]heptanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]heptanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]heptanedioate-   bis[benzoyloxymethyl]heptanedioate-   bis[hexanoyloxymethyl]heptanedioate-   bis[octanoyloxymethyl]heptanedioate-   heptanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   heptanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]octanedioate-   bis[(trifluoroacetyloxy)methyl]octanedioate-   bis[(propionyloxy)methyl]octanedioate-   bis[(butyryloxy)methyl]octanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]octanedioate-   bis[phenylacetyloxy)methyl]octanedioate-   bis[(stearoyloxy)methyl]octanedioate-   bis[(methoxycarbonyloxy)methyl]octanedioate-   bis[(ethoxycarbonyloxy)methyl]octanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]octanedioate-   bis[1-(acetyloxy)ethyl]octanedioate-   bis[1-(trifluoroacetyloxy)ethyl]octanedioate-   bis[1-(propionyloxy)ethyl]octanedioate-   bis[1-(butyryloxy)ethyl]octanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]octanedioate-   bis[1-(phenylacetyloxy)ethyl]octanedioate-   bis[1-(stearoyloxy)ethyl]octanedioate-   bis[1-(methoxycarbonyloxy)ethyl]octanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]octanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]octanedioate-   bis[benzoyloxymethyl]octanedioate-   bis[hexanoyloxymethyl]octanedioate-   bis[octanoyloxymethyl]octanedioate-   octanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   octanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]nonanedioate-   bis[(trifluoroacetyloxy)methyl]nonanedioate-   bis[(propionyloxy)methyl]nonanedioate-   bis[(butyryloxy)methyl]nonanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]nonanedioate-   bis[phenylacetyloxy)methyl]nonanedioate-   bis[(stearoyloxy)methyl]nonanedioate-   bis[(methoxycarbonyloxy)methyl]nonanedioate-   bis[(ethoxycarbonyloxy)methyl]nonanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]nonanedioate-   bis[1-(acetyloxy)ethyl]nonanedioate-   bis[1-(trifluoroacetyloxy)ethyl]nonanedioate-   bis[1-(propionyloxy)ethyl]nonanedioate-   bis[1-(butyryloxy)ethyl]nonanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]nonanedioate-   bis[1-(phenylacetyloxy)ethyl]nonanedioate-   bis[1-(stearoyloxy)ethyl]nonanedioate-   bis[1-(methoxycarbonyloxy)ethyl]nonanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]nonanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]nonanedioate-   bis[benzoyloxymethyl]nonanedioate-   bis[hexanoyloxymethyl]nonanedioate-   bis[octanoyloxymethyl]nonanedioate-   nonanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   nonanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]decanedioate-   bis[(trifluoroacetyloxy)methyl]decanedioate-   bis[(propionyloxy)methyl]decanedioate-   bis[(butyryloxy)methyl]decanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]decanedioate-   bis[phenylacetyloxy)methyl]decanedioate-   bis[(stearoyloxy)methyl]decanedioate-   bis[(methoxycarbonyloxy)methyl]decanedioate-   bis[(ethoxycarbonyloxy)methyl]decanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]decanedioate-   bis[1-(acetyloxy)ethyl]decanedioate-   bis[1-(trifluoroacetyloxy)ethyl]decanedioate-   bis[1-(propionyloxy)ethyl]decanedioate-   bis[1-(butyryloxy)ethyl]decanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]decanedioate-   bis[1-(phenylacetyloxy)ethyl]decanedioate-   bis[1-(stearoyloxy)ethyl]decanedioate-   bis[1-(methoxycarbonyloxy)ethyl]decanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]decanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]decanedioate-   bis[benzoyloxymethyl]decanedioate-   bis[hexanoyloxymethyl]decanedioate-   bis[octanoyloxymethyl]decanedioate-   decanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   decanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]undecanedioate-   bis[(trifluoroacetyloxy)methyl]undecanedioate-   bis[(propionyloxy)methyl]undecanedioate-   bis[(butyryloxy)methyl]undecanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]undecanedioate-   bis[phenylacetyloxy)methyl]undecanedioate-   bis[(stearoyloxy)methyl]undecanedioate-   bis[(methoxycarbonyloxy)methyl]undecanedioate-   bis[(ethoxycarbonyloxy)methyl]undecanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]undecanedioate-   bis[1-(acetyloxy)ethyl]undecanedioate-   bis[1-(trifluoroacetyloxy)ethyl]undecanedioate-   bis[1-(propionyloxy)ethyl]undecanedioate-   bis[1-(butyryloxy)ethyl]undecanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]undecanedioate-   bis[1-(phenylacetyloxy)ethyl]undecanedioate-   bis[1-(stearoyloxy)ethyl]undecanedioate-   bis[1-(methoxycarbonyloxy)ethyl]undecanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]undecanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]undecanedioate-   bis[benzoyloxymethyl]undecanedioate-   bis[hexanoyloxymethyl]undecanedioate-   bis[octanoyloxymethyl]undecanedioate-   undecanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl ester-   undecanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester-   bis[(acetyloxy)methyl]dodecanedioate-   bis[(trifluoroacetyloxy)methyl]dodecanedioate-   bis[(propionyloxy)methyl]dodecanedioate-   bis[(butyryloxy)methyl]dodecanedioate-   bis[(2,2-dimethylpropionyloxy)methyl]dodecanedioate-   bis[phenylacetyloxy)methyl]dodecanedioate-   bis[(stearoyloxy)methyl]dodecanedioate-   bis[(methoxycarbonyloxy)methyl]dodecanedioate-   bis[(ethoxycarbonyloxy)methyl]dodecanedioate-   bis[(phenylmethoxycarbonyloxy)methyl]dodecanedioate-   bis[1-(acetyloxy)ethyl]dodecanedioate-   bis[1-(trifluoroacetyloxy)ethyl]dodecanedioate-   bis[1-(propionyloxy)ethyl]dodecanedioate-   bis[1-(butyryloxy)ethyl]dodecanedioate-   bis[(2,2-dimethylpropionyloxy)ethyl]dodecanedioate-   bis[1-(phenylacetyloxy)ethyl]dodecanedioate-   bis[1-(stearoyloxy)ethyl]dodecanedioate-   bis[1-(methoxycarbonyloxy)ethyl]dodecanedioate-   bis[1-(ethoxycarbonyloxy)ethyl]dodecanedioate-   bis[1-(phenylmethoxycarbonyloxy)ethyl]dodecanedioate-   bis[benzoyloxymethyl]dodecanedioate-   bis[hexanoyloxymethyl]dodecanedioate-   bis[octanoyloxymethyl]dodecanedioate-   dodecanedioic acid 2,2-dimethylpropionyloxymethyl ester methyl    ester, and-   dodecanedioic acid 1-ethoxycarbonyloxy-ethyl ester methyl ester

The compounds of the invention or for use in the invention can beprepared using standard processes and procedures well-known in the artfor derivatization of multi-functional compounds, and especiallyesterification and more especially formation of acyloxymethyl esters.

As known in the literature, esterification of compounds may desirablyinvolve protection and deprotection of appropriate groups; for exampleusing technology described by McOmie in “Protective Groups in OrganicChemistry”, Plenum 1973 and T. W. Greene in “Protective Groups inOrganic Chemistry”, Wiley-Interscience 1981. Starting materials forpreparation of double esters of dicarboxylic acids according to theinvention are typically the corresponding dicarboxylic acids orderivatives thereof. Some examples of dicarboxylic acids or derivativesthereof well known in the prior art and suitable for use as startingmaterials for synthesis of double esters according to the presentinvention include:

-   adipic acid,-   pimelic acid,-   suberic acid,-   azelaic acid,-   sebacic acid,-   undecanedioic acid,-   dodecanedioic acid,-   1,11-undecanedicarboxylic acid, and-   1,12-dodecanedicarboxylic acid, all of which are commercially    available through Sigma-Aldrich.

Some dicarboxylic acid derivatives useful as intermediates in synthesisof dicarboxylic acids according to the present invention include:

-   adipic acid monomethyl ester,-   adipic acid monoethyl ester,-   suberic acid monomethyl ester,-   azelaic acid monomethyl ester, and-   sebacic acid monoethyl ester (all available through Sigma-Aldrich),-   azelaic acid dicaesium salt (see Cimecioglu et al., Makromol. Chem.    Rapid Commun. 10: 319-324 (1989)), and azelaic acid monoethyl ester.

Viewed from a further aspect, the present invention thus provides aprocess for the preparation of a compound according to the invention,said process comprising reacting a C₆₋₁₄ alkane-dicarboxylic acid or asalt or ester thereof, with an acyloxymethylating agent.

Examples of acyloxymethylating agents include compounds of formula IIR²—CO—O—CHR³—X  (II)where R² and R³ are as hereinbefore defined and X is a leaving group,e.g. a halogen atom, a hydroxyl group, a sulphonic acid ester group,etc.

Preferably the compound of formula II is reacted with a salt of adicarboxylic acid, e.g. a caesium salt, with a dicarboxylic acid inwhich one of the carboxyl groups is in a protected form (e.g.esterified), or with a dicarboxylic acid in which one or both carboxylgroups is in an activated form (e.g. acid halide form).

Thus for example the compound of formula II may be reacted with acompound of formula III

(where R¹ and n are as hereinbefore defined and R⁴ is a hydroxy or halogroup) or a salt thereof.

The reactions may conventionally be carried out in a solvent or mixtureof solvents such as acetone, diethylether, dimethylformamide,dimethylsulphoxide etc. at temperatures up to boiling point of themixture, preferably at ambient temperatures. The conditions of theesterification reactions will depend on the reagents used and theconditions may be chosen such that maximum yield of the double ester isobtained.

As mentioned earlier, the compounds of the invention or for useaccording to the invention may be in the form of pharmaceuticallyacceptable salts. Such salts can be acid addition salts withphysioloigically acceptable organic or inorganic acids if the compoundaccording to the present invention has one or more basic group, or canbe base addition salts with physioloigcally acceptable organic orinorganic bases. Typically appropriate acids include hydrochloric acid,hydrobromic acid, lactic acid, citric acid, methane sulfonic acid,maleic acid, fumaric acid, and stearinic acid. Typically appropriatebases include sodium hydroxide, potassium hydroxide, calcium hydroxideand meglumine.

Procedures for salt formation are well described in scientificliterature and patent literature.

As mentioned above, the compounds of the invention and for use accordingto the invention and their salts have valuable pharmacologicalproperties. The compounds can be used for treatment of acne, rocasea,hyperpigmentation, wound healing, actinic keratoses, basal cellcarcinoma and other dermal disease conditions. In particular thecompounds may be used to delay or prevent relapse of basal cellcarcinoma following treatment with photodynamic therapy. The compoundscan also be used to treat bacterial, viral and fungal infections and canalso be used in treatment or prevention of cancer.

Viewed from a further aspect therefore the invention provides a methodof treatment of a human or non-human (e.g. mammalian) animal subject tocombat a condition susceptible to treatment with a C₆₋₁₄alkane-dicarboxylic acid drug substance, the improvement comprisingadminstering to said subject an effective amount of said drug substancein the form of an acyloxymethyl ester thereof.

Viewed from a still further aspect the invention provides the use of anacyloxymethyl ester of a C₆₋₁₄ alkane-dicarboxylic acid drug substanceor a salt or ester thereof for the manufacture of a medicament for usein a method of treatment of a human or non-human (e.g. mammalian) animalsubject to combat a condition susceptible to treatment with saiddicarboxylic acid drug substance.

The compositions of the invention may be formulated in conventionalmanner with one or more physiologically acceptable carriers orexcipients, according to techniques well known in the art. Viewed from astill further aspect therefore the invention provides a pharmaceuticalcomposition comprising an acyloxymethyl ester of a C₆₋₁₄alkane-dicarboxylic acid or a physiologically tolerable salt or esterthereof together with at least one pharmaceutical carrier or excipient.

When appropriate, the compositions according to the invention may besterilized, e.g. by γ-radiation, strike filtration, autoclaving or heatsterilization, before or after formulation with carrier or excipient.

The compounds according to the invention can also be formulated togetherwith other pharmacologically active substances. Selection of suchsubstances will be dependent on the indication for the composition. Acomposition for treatment of acne might be a formulation of one or moreof the compounds according to this invention together with for examplebenzoyl peroxide, clindamycin, tretinoin, erythromycin, tetracyclins,adapalene, tazarotene, sulfectamide or other anti-acne agents. Acomposition for treatment of rocasea might be a formulation of one ormore of the compunds according to this invention together with othercompounds effective for treatment of rocasea; for example tetracyclinsor metronidazole. Compositions for treatment of hyperpigmentation couldbe formulated as a mixture of one or more of compounds according to thepresent invention together with glycolic acid, hydroquinone or otheragents active against hyperpigmentation of skin.

Compositions for treatment of infections (e.g. bacterial, fungal andviral infections) might contain in addition to one or more of thecompounds according to the present invention, other pharmacologicallyactive antiinfective agents; for example compositions for treatment ofbacterial infections might contain penicillins, cephalosporins, peptideantibiotics, macrolide antibiotics, antibacterial sulphonamides,vancomycin or other antibacterial agents, for example compoundsdescribed by Norrby, R. in Expert Opin. Pharmacother. 2001, 2, 293-302,Wada, K. et al in Nippon Rinsho 2001, 59, 790-94, Grandi, G. in TrendsBiotechnol. 2001, 19, 181-88, Guay, D. R. in Drugs 2001, 61, 353-64,Kopp-Hoolihan, L. In J. Am. Diet. Assoc. 2001, 101, 229-38 and 239-41,Robert, P. Y. et al in Drugs 2001, 61, 175-85, Fulton, B. et al inPaediatr. Drugs 2001, 3, 137-58, Bhanot, S. K. et al in Curr. Pharm.Des. 2001, 7, 311-35, Krasemann, C. et al in Clin. Infect Dis. 2001, 32Supplement S51-63, Bush, K. et al in Curr. Opin. Investig. Drugs 2000,1, 22-30, Rubin, B. K. et al in Curr. Opin. Investig. Drugs 2000, 1,169-72, Leung, W. K. et al in Expert Opin. Pharmacother. 2000, 1,507-14, Periti, P. in Expert Opin. Pharmacother. 2000, 1, 1203-17,Anonymus in Nat. Biotechnol. 2000, 18 Supplement, IT 24-6, Dbaibo, G. S.in J. Med. Liban. 2000, 48, 177-81, Muller, M. et al in Cell. Mol. LifeSci. 1999, 56, 280-5, Gray, C. P. et al in Cell Mol. Life-Sci. 1999, 56,779-87, Bax, R. et al in Int. J. Antimicrob. Agents 2000, 16, 51-9 andBush, K. et al in Curr. Opin. Chem. Biol. 2000, 4, 433-9 or inreferences therein.

Compositions according to the present invention for treatment of fungalinfections might for example contain nystatin, amphothericin,griseofulvin, imidazole derivatives and triazole derivatives likechlotriamazole, micronazole, econazole, ketoconazole and bifonazole andother agents like, for example, antifungal agents described byEspinel-Ingroff, A. et al in Mycopathologica 2001, 150, 101-15, Yang, Y.L. et al in J. Microbiol. Immunol. Infect. 2001, 34, 79-86, Willems, L.et al in J. Clin. Pharm. Ther. 2001, 26, 159-69, Worthen, D. R. et al inDrug Dev. Ind. Pharm. 2001, 27, 277-186, Dupont, B. in Rev. Prat. 2001,51, 752-7, Kauffman, C. A. in AIDS Patient Care STDS II Supplement 1,S18-21, Rex, J. H. et al in Clin. Infect. Dis. 2001, 32, 1191-200, Hann,I. M. et al in Int. J. Antimicrob. Agents 2001, 17, 161-9, Arikan, S. etal in Curr. Pharm. Des. 2001, 7, 393-415, Kroting, H. C. et al inHautarzi 2001, 52, 91-7, Fringuelli, R. et al in J. Chemother. 2001, 13,9-14, Anonymous in Nat. Biotechnol. 2000, 18, Suppl. IT 24-6, Ellepola,A. N. et al in Dent. Update 2000, 27, 165-70 and 172-4, Ellepola, A. N.et al in Dent. Update 2000, 27, 111-2 and 114-6, Neely, M. N. et al inEur. J. Microbiol. Infect. Dis. 2000, 19, 897-914, Walsh, T. J. et al inMed. Mycol. 2000, 38, Suppl. 1, 335-47, Graybill, J. R. et al in Med.Mycol. 2000, 38, Suppl. 1, 323-33 and Fingquelievich, J. L. et al inMed. Mycol. 2000, 38 Suppl. 1, 317-22 or in references therein.

Compositions according to the present invention for treatment of viralinfections might for example contain agents for treatment of DNA virusesor RNA viruses. Typical such compounds that could be included incompositions according to the present invention can be acyclovir,ganciclovir, valaciclovir, ribavirin, foscarnet, protease inhibitorslike saquinavir, indinavir, ritonavir and nelfinavir, reversetranscriptase inhibitors like zidovudine, didanosine, zulcitabine,stavudine, lamivudine, abakavir, nevirapine and etavirenze andneuramidase inhibitors like zanamivire or other antiviral agents, forexample agents described by Delaney, W. E. et al in Antivir. Chem.Chemother, 2001, 12, 1-35, Buss, N. et al in Antivir. Ther. 2001, 6,1-7, Roberts, N. A. et al in Prog. Drug Res. 2001, 56, 195-237, Field,H. J. in J. Clin. Virol. 2001, 21, 261-9, Bowers, M. in BETA 1996, Jun.19-22, Mediratta, P. K. et al in Indian J. Med. Sci. 2000, 54, 485-90,Fleming, D. M. in Int. J. Clin. Pract. 2001, 55, 189-35, Mahalingam, S.et al in Bioessays 2001, 23, 428-35, Nabel. G. J. in Nature 2001, 410(6831), 1002-7, Lever, A. M. in Sex Transm. Infect. 2001, 77, 93-6,McClellan et al in Drugs 2001, 61, 263-843 and Brown, T. J. et al inDermatol. Clin. 2001, 19, 23-34 and references therein.

A composition for treatment or prevention of cancer-related diseasesmight for example be a formulation of one or more of the compoundsaccording to this invention together with other agents for treatment ofprevention of cancer. Typical substances for treatment of cancer couldfor example be alkylating agents like for example cyclophosphamide,chlorambucile, melfalane, iphosphamide, treosulfane, tiotepa,carmustine, iomustine, fotemustine, temozolomide, antimetabolites likefor example metotrexate, raltitrexed, mercaptopurine, clodribine,fludarabine, cytarabine, fluorouracil, gemcitabin, plant alkaloides andother natural products like for example vinblastine, vincristine,vinorelbine, etoposid, paclitaxel, docetaxel, cytotoxic antibiotics likefor example daktinomycine, doxorubicine, daunorubicine, epirubicine,idarubicine, mitoxantrone, bleomycine, plikamycine, mitomycine and othercytotoxic agents like for example cisplatin, carboplatin, amsakrine,altretamine, estramustine, topotecane, irinotecane, verteporfine,hormones, hormone-like substances and other substances described byStachel, S. J. et al in Curr. Pharm. Des. 2001, 7, 1277-90, Gueritte, F.in Curr. Pharm. Des. 2001, 7, 1229-1249, de Groot, F. M. et al in Curr.Med. Chem. 2001, 8, 1093-1122, Sebti, S. M. et al in Oncogene 2000, 19,6584-93, Ramirez De Molina, A. et al in Int. J. Oncol. 2001, 19, 5-17,Crul, M. et al in Anticancer Drugs 2001, 12, 163-84, Chamberlain, R. S.et al in Expert Opin. Pharmacother. 2000, 1, 603-14, Rowley, P. T. et alin Anticancer Res. 2000, 20, 4419-29, Schirner, M. in Cancer MetastasisRev. 2000, 19, 67-73, Hofman, J. in Rev. Physiol. Biochem. Pharmacol.2001, 142, 1-96, Goss, P. E. et al in J. Clin. Oncol. 2001, 19, 881-94,Hadi, S. M. et al in IUBMB Life 2000, 50, 167-71, Perry, P. J. et al inExpert Opin. Investig. Drugs 1999, 8, 1981-2008, Koki, A. T. et al inExpert Opin, Investig. Drugs 1999, 8, 1623-1638 and Kushner, D. M. et alin Curr. Oncol. Rep. 2000, 2, 23-30 and references therein.

Typical substances for prevention of cancer which might be included inthe compositions of the invention could for example be Vitamin E andother agents with antioxidative properties and COX-2 inhibitors.

The compositions according to the invention may be administeredtopically, orally, rectally or systemically depending on the indicationand choice of substance or substances.

The compositions may be presented in a form adapted for enteral orparenteral administration. Compositions for enteral administration canfor example be plain or coated tablets, sustained release tablets, softcapsules, hard capsules, suppositories, suspensions and solutions of theactive component(s) optionally together with one or more inertconventional carriers.

Compositions for parenteral administration could for example beformulations for intradermal, subcutaneous, intraperitoneal orintravenous injection or infusion. Other parenteral compositions includecompositions for topical administration; including compositions foradministration not only to skin but to mucosa and administered to hair.Such topical compositions include gels, creams, ointments, shampoos,soaps, spray, lotions, salves, aerosols and other pharmaceuticalformulations for topical use.

All compositions might optionally be formulated with one or more inertcarriers and/or diluents; e.g. water, water/ethanol, ethanol,water/glycerol, polyethyleneglycol, sodium chloride, glucose, sucrose,lactose, corn starch, microcrystalline cellulose, sorbitol, magnesiumstearate, alcohols, polyvinylpyrroidone, fatty acids, fat, fat wax, EDTAand calcium chloride.

The compositions may additionally include wetting agents, lubricationagents, emulsifying agents, suspending agents, preserving agents,sweetening agents, flavoring agents and absorption enchancers.

The compositions may be in the form of microemulsions, nanoparticles,microspheres, niosomes or liposomes.

Compositions in which the drug substance is in a non-aqueous environment(e.g. an ointment) are especially preferred.

The concentration of the active compound(s) as described hereinbefore inthe compositions, depends upon several factors, including mode ofadministration, chemical nature of the compounds, clinical indicationand condition of the patient. The concentration will therefore vary overa large range. Generally, however, active agent concentration ranges of0.005 to 100%, e.g. 0.01 to 70%, commercially 0.05 to 50%, andpreferably 0.1 to 20% (w/w) are suitable. Typically compositions withhigh concentrations of dicarboxylic acid double esters (>10%) accordingto the present invention will include oral products like capsules ortablets, while other composition forms will normally have lowerconcentration (<10%) of the active compound(s).

The compositions according to the present invention are preferably in aready to use form; however concentrates and kits may also be used. Sucha kit might contain two or more containers, e.g.

-   -   a) a first container containing a dicarboxylic acid double ester        or a pharmaceutically acceptable salt thereof; and    -   b) a second container containing a solvent for dissolution or        dispersion of the contents of the first container prior to use.

This kit formulation might typically be used where the dicarboxylic aciddouble ester or other pharmaceutically active substances in thecomposition are unstable in a ready to use formulation (e.g. shelf lifeis less than 6 months or preferably less than 12 months).

It is believed that presentation as an acyloxymethyl ester may bebeneficial for other dicarboxylic acid drug substances, especially thosewith poor transdermal uptake or rapid urinary excretion and theinvention is deemed to extend to other dicarboxylic acid drugsubstances, especially alkane, azaalkane, thiaalkane and oxaalkanedicarboxylic acids.

The invention willnow be described in more detail in the followingnon-limiting Examples:

Synthesis of Chloromethyl Ester Starting Materials

Chloromethyl pivalate and 1-chloroethyl ethyl pivalate are commerciallyavailable. Other chloromethyl esters were synthesised by reactingparaformaldehyde with acid chlorides.

EXAMPLE A

Synthesis of Chloromethyl Benzoate

Benzoyl chloride (14.05 g, 0.10 mol) and paraformaldehyde (3.6 g, 0.12mol) were heated at 120° C. until the latter disappeared (about 2hours). The reaction mixture was distilled in vacuo and chloromethylbenzoate was obtained as a colourless oil (b.p. 116° C., 10 mbar).¹H-NMR (CDCl₃) δ 8.18-7.46 (m, 5H), 6.00 (s, 2H). ¹³C-NMR (CDCl₃) δ133.89, 131.36, 130.01, 128.91, 128.54, 69.21.

EXAMPLE B

Synthesis of Chloromethyl Butyrate

Butyryl chloride (10.65 g, 0.10 mol) and paraformaldehyde (3.60 g, 0.12mol) were heated at 120° C. until the latter disappeared (about 2hours). The reaction mixture was distilled in vacuo and chloromethylbutyrate was obtained as a colourless oil (b.p. 90° C., 25 mbar). ¹H-NMR(CDCl₃) δ 5.67 (s, 2H), 2.37-2.29 (m, 2H), 1.64-1.58 (m, 2H), 1.26 (s,8H).

EXAMPLE C

Synthesis of Chloromethyl Hexanoate

Thionyl chloride (14.27 g, 0.12 mmol) was added dropwise to hexanoicacid (11.61 g, 0.10 mmol) and the reaction mixture was heated at 70° C.for 24 hours. The reaction mixture containing hexanoyl chloride was notfurther purified and paraformaldehyde (3.60 g, 0.12 mol) was added andthe reaction mixture heated at 120° C. until the latter disappeared(about 2 hours). The reaction mixture was distilled in vacuo andchloromethyl hexanoate was obtained as a colourless oil (b.p. 118° C.,25 mbar). ¹H-NMR (CDCl₃) δ 5.67 (s, 2H), 2.37-2.29 (m, 2H), 1.65-1.58(m, 2H), 1.31-1.26 (m, 4H), 0.88 (t, 3H). ¹³C-NMR(CDCl₃) δ 179.89,171.77, 68.53, 33.95, 31.18, 24.34, 22.26, 13.83.

EXAMPLE D

Synthesis of Chloromethyl Octanoate

Octanoyl chloride (16.26 g, 0.10 mol) and paraformaldehyde (3.6 g, 0.12mol) were heated at 120° C. until the latter disappeared (about 2hours). The reaction mixture was distilled in vacuo and chloromethyloctanoate was obtained as a colourless oil (b.p. 140° C., 25 mbar).¹H-NMR (CDCl₃) δ 5.67 (s, 2H), 2.37-2.29 (m, 2H), 1.64-1.58 (m, 2H),1.26 (s, 2H), 0.84 (t, 3H). ¹³C-NMR(CDCl₃) δ 171.75, 162.30, 68.51,33.94, 31.55, 28.97, 28.85, 28.80, 24.64, 24.50, 22.52, 13.98.

EXAMPLE E

Synthesis of Hexyl 2-Chloroacetate Chloroacetoyl chloride (2.48 g, 22.00mmol) in CH₂Cl₂ (10 ml) was added dropwise to a solution of hexan-1-ol(2.04 g, 20.00 mmol) and triethylamine (2.22 g, 22.00 mmol) in CH₂Cl₂(25 ml). The reaction mixture was stirred at room temperature for 3hours, evaporated in vacuo and then diluted with diethyl ether (25 ml).The organic layer washed with saturated NaHCO₃ (3×10 ml), dried withMgSO₄ and filtered. Evaporation in vacuo gave the product as a red oil.¹H-NMR (CDCl₃) δ 4.01 (s, 2H), 1.63-1.53 (m, 2H), 1.28-1.13 (m, 8H),0.85 (t, 3H). ¹³C-NMR(CDCl₃) δ 167.36, 66.36, 40.86, 31.28, 28.36,25.36, 22.43, 13.88.

General Procedure for the Synthesis of Esters of Alkanedioic Acids

A heterogeneous solution of Cs₂CO₃, NaI (as catalyst) and alkanedioicacid in THF was stirred for ½ hour at 60° C. A chloroalkylester in THFwas added dropwise to the solution and stirred at 60° C. for 48 hours.The reaction mixture was cooled to room temperature, evaporated in vacuoand diethyl ether was added to the residue. The organic layer was washedwith saturated NaHCO₃, filtered and dried with MgSO₄. Evaporation invacuo gave the expected product.

EXAMPLE 1 Bis[[(2,2-dimethylpropanoyl)oxy]methyl]nonanedioate (CompoundI)

Caesium carbonate (32.6 g; 0.120 mol) was added to a stirred solution ofnonanedioic acid (9.4 g; 50.0 mmol), chloromethyl pivalate (15.1 g; 0.10mmol), and NaI (0,5 g; 3.3 mmol) in dry N,N-dimethylformamide (50 mL).The mixture was stirred for 2 days at ca. 40° C. (bath temperature)under argon. Excess solvent was evaporated off at ca. 35° C. (bathtemperature) and 5 to 1 mm Hg. The residue was dissolved in water (50mL) and diethyl ether (25 mL). The aqueous portion was extracted withether (1×15 mL) and the combined ether solutions were washed withsaturated NaCl solution (1×10 mL) and dried (Na₂SO₄). Filtration andevaporation left 12.34 g (59%) after pumping out to 0.2 mm Hg. ¹H NMR(200 MHz; CDCl₃): δ 1.20 (20H, s), 1.32 (4H, s), 1.63 (4H, m), 2.35 (4H,t, J=7.4 Hz), 5.76 (4H, d, J=2.8 Hz). ¹³C NMR (50 MHz; CDCl₃): δ 24.58,26.84, 28.80, 29.01, 33.92, 38.73, 79.22, 164.87, 172.29, MS(ES):439.3[M+Na]⁺.

EXAMPLE 2

Creams Containing Compound I

Three creams containing compound I (2%, 5% and 10% w/w) from Example 1were prepared by mixing in compound I in Unguentum Merck® using a mortarand pestle.

EXAMPLE 3

Clinical Testing of Creams from Example 2

Indication: Acne Rocasea

A 47 year old male patient with more than 20 years history of AcneRocasea in the face (more than 20 cm² located below eyes and aroundnose) administered 10% cream (Example 2) twice daily (morning andevening). The symptoms were reduced after 2-3 days and the patient wasfree from visual symptoms after 1 week of treatment. The patientcontinued to use 2% cream once every 2-3 weeks and has been free fromsymptoms for 9 months. The patient had previously used oraloxytetracycline capsules and 1% metronidazole cream with no majorclinical effect.

EXAMPLE 4

Clinical Testing of Creams from Example 2

Indication: Wound Healing

A 77 year old male patient with several wounds and extreme dry skin inthe forehead and scalp had tried out different moisturizers without anyhealing effect. After approximately one week of daily treatment with 2%cream (Example 2), the patient observed a normalization of the skin withonly two wounds left. The patient observed some new formation of hair atthe area of treatment.

EXAMPLE 5

Ointment Containing Compound I

An ointment containing 10% wt of Compound I from Example 1 was preparedby mixing compound I and a water-free ointment base (Vaseline®/albumin)in a pestle and mortar.

EXAMPLE 6 Synthesis ofbis-[[2,2-dimethylpropionyl]oxymethyl]dodecanedioate

A heterogeneous solution of Cs₂CO₃ (13.03 g, 40 mmol), NaI (200 mg, 1.3mmol) and dodecanedioic acid (4.60 g, 20 mmol) in THF (40 ml) wasstirred for % hour at 60° C. Chloromethyl pivalate (6.02 g, 40 mmol) inTHF (10 ml) was added dropwise to the solution and stirred at 60° C. for48 hours. The reaction mixture was cooled to room temperature andevaporated in vacuo. Diethyl ether (50 ml) was added and the residue waswashed with saturated NaHCO₃ (3×25 ml), dried with MgSO₄ and filtered.Evaporation in vacuo gave the product as a colourless oil (5.13 g,56.0%). MS (ES): 481.4 [M+Na]⁺. ¹H-NMR (CDCl₃) δ 5.95 (s, 4H), 2.51-2.47(m, 4H), 1.58-1.52 (m, 4H), 1.21-1.15 (m, 30H). ¹³C-NMR δ 176.30,172.50, 79.13, 38.69, 33.91, 29.26, 28.87, 26.76, 25.54, 24.61.

EXAMPLE 7 Synthesis of bis-[1-[ethoxycarbonyloxy]-ethyl]nonanedioate

A heterogeneous solution of Cs₂CO₃ (13.03 g, 40 mmol), NaI (200 mg, 1.3mmol) and nonanedioic acid (3.76 g, 20 mmol) in THF (40 ml) was stirredfor % hour at 60° C. 1-Chloroethyl ethyl carbonate (6.10 g, 40 mmol) inTHF (10 ml) was dropwise added to the solution and stirred at 60° C. for48 hours. The reaction mixture was cooled to room temperature andevaporated in vacuo. Diethyl ether (50 ml) was added and the residue waswashed with saturated NaHCO₃ (3×25 ml), dried with MgSO₄ and filtered.Evaporation in vacuo gave the product as a yellow oil (3.83 g, 45.6%).¹H-NMR (CDCl₃) δ 6.39 (q, 2H), 4.26-4.16 (m, 4H), 2.31-2.25 (m,4H)1.55-1.58 (m, 4H), 1.46 (d, 2H), 1.32-1.18 (m, 12H). ¹³C-NMR (CDCl₃)δ 178.35, 171.63, 152.97, 91.08, 64.89, 33.91, 28.75, 24.53, 19.49,14.04.

EXAMPLE 8

Synthesis of Bis-[1-[ethoxycarbonyloxy]ethyl]dodecanedioate

A heterogeneous solution of Cs₂CO₃ (13.03 g, 40 mmol), NaI (200 mg, 1.3mmol) and dodecanedioic acid (4.60 g, 20 mmol) in THF (40 ml) wasstirred for ½ hour at 60° C. 1-Chloroethyl ethyl carbonate (6.10 g, 40mmol) in THF (10 ml) was added dropwise added to the solution andstirred at 60° C. for 48 hours. The reaction mixture was cooled to roomtemperature and evaporated in vacuo. Diethyl ether (50 ml) was added andthe residue washed with saturated NaHCO₃ (3×25 ml), dried with MgSO₄ andfiltered. Evaporation in vacuo gave the product as a yellow oil (4.25 g,47.5%). ¹H-NMR (CDCl₃) δ 8.39 (q, 2H), 6.27-6.10 (m, 4H), 4.35-4.24 (m,4H), 3.60-3.57 (4H), 3.46-3.43 (d, 6H), 3.32-3.22 (m, 18H).

EXAMPLE 9 Synthesis of nonanedioic acid 2,2-dimethyl-propionyloxymethylester methyl ester

A heterogeneous solution of Cs₂CO₃ (1.30 g, 4.0 mmol), NaI (30 mg, 0.20mmol) and nonanedioic acid monomethyl ester (0.95 g, 4.0 mmol) in THF(15 ml) was stirred for ½ hour at 60° C. Chloromethyl pivalate (0.60 g,4.0 mmol) in THF (5 ml) was added dropwise to the solution and stirredat 60° C. for 48 hours. The reaction mixture was cooled to roomtemperature and evaporated in vacuo. Diethyl ether (25 ml) was added,and the residue was washed with saturated NaHCO₃ (3×15 ml), dried withMgSO₄ and filtered. Evaporation in vacuo gave the product as acolourless oil (0.85 g, 67.5%). ¹H-NMR (CDCl₃) δ 5.74 (s, 2H), 3.66 (s,3H), 2.38-2.26 (m, 4H), 1.63-1.56 (m, 4H), 1.31 (s, 6H), 1.21 (s, 9H).¹³C-NMR (CDCl₃) δ 177.05, 174.06, 172.23, 79.19, 51.33, 38.63, 33.90.33.82, 28.78, 28.72, 28.64, 26.74, 24.73, 24.47.

EXAMPLE 10 Synthesis of nonanedioic acid 1-(ethoxycarbonyloxy)-ethylester methyl ester

A heterogeneous solution of Cs₂CO₃ (1.30 g, 4.0 mmol), NaI (30 mg, 0.20mmol) and nonanedioic acid monomethyl ester (0.95 g, 4.0 mmol) in THF(15 ml) was stirred for M hour at 60° C. 1-Chloroethyl ethyl carbonate(0.61 g, 4.0 mmol) in THF (5 ml) was added dropwise to the solution andstirred at 60° C. for 48 hours. The reaction mixture was cooled to roomtemperature and evaporated in vacuo. Diethyl ether (25 ml) was added andthe residue was washed with saturated NaHCO₃ (3×25 ml), dried with MgSO₄and filtered. Evaporation in vacuo gave the product as a colourless oil(0.96 g, 75.1%). ¹H-NMR (CDCl₃) δ 6.74 (q, 1H), 4.19 (q, 2H), 3.64 (s,3H), 2.34-2.24 (m, 4H), 1.63-1.53 (m, 4H), 1.49 (d, 2H), 1.33-1.24 (m,9H). ¹³C-NMR (CDCl₃) δ 174.55, 172.04, 162.92, 153.39, 91.48, 64.75,51.79, 36.85, 34.37, 31.78, 29.24, 25.19, 24.82, 19.09, 14.48.

EXAMPLE 11 Synthesis of bis-(benzoyloxymethyl) nonanedioate

A heterogeneous solution of Cs₂CO₃ (3.25 g, 10.00 mmol), NaI (50 mg,0.33 mmol) and nonanedioic acid (0.94 g, 5.00 mmol) in THF (20 ml) wasstirred for ½ hour at 60° C. Chloromethyl benzoate (1.70 g, 10 mmol) inTHF (10 ml) was added dropwise to the solution and stirred at 60° C. for48 hours. The reaction mixture was cooled to room temperature andevaporated in vacuo. Diethyl ether (25 ml) was added and the residue waswashed with saturated NaHCO₃ (3×15 ml), dried with MgSO₄ and filtered.Evaporation in vacuo gave the product as a white solid (1.76 g, 77.2%).¹H-NMR (CDCl₃) δ 8.09-7.39 (m, 10H), 5.97 (s 4H), 2.37-2.29 (m, 4H),1.61-1.56 (m, 4H), 1.28-1.25 (m, 6H). ¹³H-NMR (CDCl₃) δ 172.65, 165.20,133.63, 130.01, 128.92, 128.44, 79.71, 33.84, 28.70, 28.65, 24.42.

EXAMPLE 12 Synthesis of bis-(butanoyloxymethyl)nonanedioate

A heterogeneous solution of Cs₂CO₃ (2.60 g, 8.00 mmol), NaI (30 mg, 0.20mmol) and nonanedioic acid (0.94 g, 4.00 mmol) in THF (15 ml) wasstirred for ½ hour at 60° C. Chloromethyl butanoate (1.09 g, 8.00 mmol)in THF (5 ml) was added dropwise added to the solution and stirred at60° C. for 48 hours. The reaction mixture was cooled to room temperatureand evaporated in vacuo. Diethyl ether (25 ml) was added and the residuewas washed with saturated NaHCO₃ (3×05 ml), dried with MgSO₄ andfiltered. Evaporation in vacuo gave the product as a colourless oil(0.76 g, 49.0%). ¹H-NMR (CDCl₃) δ 5.70 (s, 4H), 2.29 (t, 8H), 1.65-1.55(m, 8H), 1.27 (s, 6H), 0.90 (t, 6H). ¹³C-NMR (CDCl₃) δ 172.31, 162.50,78.97, 35.73, 33.81, 28.67, 24.41, 18.05, 13.43.

EXAMPLE 13 Synthesis of bis-(hexanoyloxymethyl) nonanedioate

A heterogeneous solution of Cs₂CO₃ (1.30 g, 4.00 mmol), NaI (20 mg, 0.13mmol) and nonanedioic acid (0.37 g, 2.00 mmol) in THF (15 ml) wasstirred for % hour at 60° C. Chloromethyl hexanoate (0.65 g, 4.00 mmol)in THF (5 ml) was added dropwise added to the solution and stirred at60° C. for 48 hours. The reaction mixture was cooled to room temperatureand evaporated in vacuo. Diethyl ether (20 ml) was added and the residuewas washed with saturated NaHCO₃ (3×10 ml), dried with MgSO₄ andfiltered. Evaporation in vacuo gave the product as a colourless oil(0.91 g, 51.9%). ¹H-NMR (CDCl₃) δ 5.72 (s, 4H), 2.43-2.32 (m, 8H),1.75-1.64 (m, 8H), 1.36-1.33 (m, 14H), 0.91 (t, 6H). ¹³C-NMR (CDCl₃) δ172.80, 162.72, 79.40, 34.49, 34.30, 34.25, 31.51, 29.19, 29.12, 24.85,24.66, 22.62, 14.22.

EXAMPLE 14 Synthesis of bis-(octanoyloxymethyl) nonanedioate

A heterogeneous solution of Cs₂CO₃ (2.60 g, 4.00 mmol), NaI (30 mg, 0.20mmol) and nonanedioic acid (0.75 g, 4.00 mmol) in THF (20 ml) wasstirred for ½ hour at 60° C. Chloromethyl octanoate (1.53 g, 8.00 mmol)in THF (5 ml) was added dropwise added to the solution and stirred at60° C. for 48 hours. The reaction mixture was cooled to room temperatureand evaporated in vacuo. Diethyl ether (20 ml) was added and the residuewas washed with saturated NaHCO₃ (3×15 ml), dried with MgSO₄ andfiltered. Evaporation in vacuo gave the product as a colourless oil(0,95 g, 47.9%). ¹H-NMR (CDCl₃) δ 5.76 (s, 4H), 2.37 (t, 8H), 1.65 (t,8H), 1.30 (s br, 22H), 90 (t, 6H). ¹³C-NMR (CDCl₃) δ 172.89, 62.32,79.44, 34.35, 34.26, 31.99, 29.32, 29.23, 29.14, 24.99, 24.86, 22.94,14.41.

EXAMPLE 15

Antibacterial Activity of Azelaic Acid and Azelaic Acid Derivatives

The antibacterial effects of azelaic acid and the azelaic acidderivatives of Examples 7, 12 and 13 on Staphylococcus aureus weretested on agar gels. All the derivatives showed large inhibiting zoneswhile azelaic acid in the same amount (10 mg) showed no inhibitingeffect.

The derivatives showed also high activity against Enterococcus faecalis,Streptococcus pyogenes and Staphylococcus epidermida.

EXAMPLE 16

Clinical Testing of Creams of Example 2

Indication: Skin Cancer

A 76 year old woman with skin cancer in the face (one lesion above thenose) was treated with photodynamic therapy (5-ALA methyl ester,available from Photocure ASA, Oslo, Norway). The outcome of thetreatment was very good. After about one year she observed a new lesionin the same area. She has now been using a 5% cream (Example 2) on aweekly basis for about 1.5 years to keep the development of the diseaseunder control.

EXAMPLE 17

Clinical Testing of Creams from Example 2

Safety

The cream of Example 2 has been tested for treatment of various skindiseases for about 2 years (see previous Examples). No local or systemicside effects have been observed. The patient from Example 3 has beentreated on a daily basis for weeks with the cream (2-10%) without anysign of toxicity.

1. (canceled)
 2. (canceled)
 3. A compound of formula I

(where n is an integer having a value of 4 to 12 R¹ is hydrogen, anoptionally substituted, optionally unsaturated C₁₋₁₅ alkyl group, or agroup —CHR³—O—CO—R²; each R² independently is an optionally substituted,optionally unsaturated C₁₋₁₅ alkyl or alkoxy group, an aryl, alkaryl,aralkyl, aryloxy, alkaryloxy or aralkoxy group having up to 16 carbons,or together with the R³ γ to it is a 2 to 5 backbone atom bridginggroup; and each R³ independently is hydrogen, an optionally substituted,optionally unsaturated C₁₋₁₅ alkyl group, a group R²—CO—O— or togetherwith R² forms a 2 to 5 backbone atom bridging group, or aphysiologically tolerable salt thereof.
 4. The compound of claim 3wherein n is 6, 7 or 8, R¹ is a C₁₋₁₀ alkyl group or a group of formula—CHR³—O—CO—R², R³ is hydrogen or a C₁₋₃ alkyl group, and each R² is amethyl, ethyl, propyl, butyl, pentyl, benzyl, methoxy, ethoxy,propyloxy, butoxy, pentoxy or benzyloxy group, or a physiologicallytolerable salt thereof.
 5. The compound of claim 3 wherein n is 7, 8, 9or 10; R² is C₂₋₆ alkyl or alkoxy or phenyl; R³ is H or methyl; and R¹is CH₃ or CHR³OCOR², or a physiologically tolerable salt thereof. 6-9.(canceled)
 10. The compound of claim 3 wherein n is 6, 7 or
 8. 11. Thecompound of claim 3 wherein n is
 7. 12. A process for the preparation ofa compound according to claim 3, said process comprising reacting aC₄₋₁₂ alkane-dicarboxylic acid or a salt or ester thereof, with anacyloxymethylating agent.
 13. The process of claim 12, said processcomprising reacting a compound of formula III

where n is an integer having a value of 4 to 12, R¹ is hydrogen, anoptionally substituted, optionally unsaturated C₁₋₁₅ alkyl group, or agroup —CHR³—O—CO—R²; R² is an optionally substituted, optionallyunsaturated C₁₋₁₅ alkyl or alkoxy group, an aryl, alkaryl, aralkyl,aryloxy, alkaryloxy or aralkoxy group having up to 16 carbons, ortogether with the R³ γ to it is a 2 to 5 backbone atom bridging group;and R³ independently is hydrogen, an optionally substituted, optionallyunsaturated C₁₋₅ alkyl group, a group R²—CO—O— or together with R² formsa bridging group, and R⁴ is a hydroxy or halo group; or a salt thereofwith an acyloxymethylating agent of formula IIR²—CO—O—CHR³—X  (Id wherein R² is an optionally substituted, optionallyunsaturated C₁₋₁₅ alkyl or alkoxy group, an aryl, alkaryl, aralkyl,aryloxy, alkaryloxy or aralkoxy group having up to 16 carbons, ortogether with the R³ γ to it is a 2 to 5 backbone atom bridging group;and R³ independently is hydrogen, an optionally substituted, optionallyunsaturated C₁₋₁₅ alkyl group, a group R²—CO—O— or together with R²forms a bridging group; and X is a leaving group.
 14. The process ofclaim 13, wherein the leaving group is a halogen atom, a hydroxyl group,or a sulphonic acid ester group.
 15. A pharmaceutical compositioncomprising a compound of claim 3 or a physiologically tolerable salt orester thereof together with at least one pharmaceutical carrier orexcipient.
 16. The use of a compound of claim 3 as an acyloxymethylester of an n-alkane-α,ω-dicarboxylic acid drug substance or a salt orester thereof for the manufacture of a medicament for use in a method oftreatment of a human or non-human animal subject to combat a conditionsusceptible to treatment with said dicarboxylic acid drug substancecomprising formulating the compound with one or more physiologicallyacceptable carriers or excipients.
 17. A method of treatment of a humanor non-human animal subject to combat a condition susceptible totreatment with an n-alkane-α,ω-dicarboxylic acid drug substance, theimprovement comprising administering to said subject an effective amountof said drug substance in the form of compound of claim 3 or aphysiologically tolerable salt thereof.
 18. The method of claim 17,wherein the compound or the physiologically tolerable salt thereof isadministered as a pharmaceutical composition comprising the compound orthe physiologically tolerable salt thereof together with at least onepharmaceutical carrier or excipient
 19. The method of claim 17, whereinthe condition is acne, rocasea, hyperpigmentation, wound healing,actinic keratoses, basal cell carcinoma, or a bacterial, viral or fungalinfection, or cancer.
 20. The method of claim 18, wherein the conditionis acne, rocasea, hyperpigmentation, wound healing, actinic keratoses,basal cell carcinoma, or a bacterial, viral or fungal infection, orcancer.
 21. Use of an acyloxymethyl ester of a C₆₋₁₄ alkane-dicarboxylicacid drug substance or a salt or ester thereof for the manufacture of amedicament for use in a method of treatment of acne, rocasea,hyperpigmentation, wound healing, actinic keratoses, basal cellcarcinoma, or a bacterial, viral or fungal infection, or in a method oftreatment or prevention of cancer comprising formulating theacyloxymethyl ester of the C₆₋₁₄ alkane-dicarboxylic acid with one ormore physiologically acceptable carriers or excipients.
 22. A method oftreatment of a human or non-human animal subject to combat acne,rocasea, hyperpigmentation, wound healing, actinic keratoses, basal cellcarcinoma, a bacterial, viral or fungal infection, or cancer, theimprovement comprising administering to said subject an effective amountof an acyloxymethyl ester of a C₆₋₁₄ alkane-dicarboxylic acid drugsubstance or a physiologically tolerable salt or ester thereof.
 23. Themethod of claim 22, wherein the acyloxymethyl ester or thephysiologically tolerable salt thereof is administered as apharmaceutical composition comprising the acyloxymethyl ester or thephysiologically tolerable salt thereof together with at least onepharmaceutical carrier or excipient.